The long-term objective of this project is to elucidate the neuronal mechanisms of learning and memory in a simple organism, Aplysia californica. The defensive withdrawal system of this invertebrate constitutes an important model system for this purpose. The reflex exhibits several simple forms of learning, including classical conditioning. Furthermore, the neuronal circuitry that underlies the reflex is relatively well understood. A central component of this circuitry is the synaptic connection between the sensory and motor neurons that mediate the reflex. Changes in the strength of the sensorimotor synapse have been shown to parallel learning by this animal. The sensorimotor synapse is therefore an advantageous starting point for a cellular analysis of learning in Aplysia. The project will focus on a form of synaptic plasticity that has long been thought by neuroscientists to mediate learning and memory in the vertebrate brain-Hebbian potentiation. Due to the brain's tremendous complexity, however, as well as to the sophistication of the forms of learning exhibited by vertebrates, it has proved difficult to convincingly link Hebbian potentiation and memory. Recently, it has been shown that sensorimotor synapses of Aplysia exhibit Hebbian potentiation. This fact permits the use of Aplysia for a reductionist analysis of the role of Hebbian potentiation in a simple form of associative learning-classical conditioning of the withdrawal reflex. The goal of the project will be: (1) to attempt to provide evidence that Hebbian plasticity plays a role in classical conditioning through the use of pharmacological antagonists of N-methyl-D-aspartate receptors, the receptor type known to mediate Hebbian plasticity; (2) to determine whether classical conditioning involves an interaction between Hebbian plasticity and synaptic competition; (3) to determine whether classical conditioning involves an interaction between Hebbian plasticity and cellular pathways activated by monoaminergic transmitters; and (4) to attempt to discover the long-term cellular changes that maintain Hebbian potentiation. It is expected that the findings from the proposed research will contribute to an understanding of the processes that underline learning and memory. Such an understanding will serve as a basis for treatments to ameliorate diseases of memory, such as Alzheimer's.